SHANGHAI – Beigene Ltd. nabbed the Asia-Pacific rights to sitravatinib from Mirati Therapeutics Inc. in a $10 million cash deal, valued at $123 million when additional milestones roll in. The Beijing-based firm also recently closed a public offering of about $800 million to support its growing immuno-oncology pipeline.

Currently being studied in two trials in the U.S. with potential in non-small-cell lung cancer, sitravatinib is a tyrosine kinase inhibitor that has demonstrated potent inhibition of receptor tyrosine kinases (RTKs) both as a single agent and when combined with approved PD-1 drug Opdivo (nivolumab, Bristol-Myers Squibb Co.) in lung cancer patients.

Beigene, one of China's leading clinical-stage immuno-oncology companies, was founded on the belief that combinations will make or break the success of its pipeline. Until recently however, the biotech has been better known for out-licensing deals – such as brokering a $1.4 billion deal with Celgene Corp., of Summit, N.J., last summer, handing over the ex-China rights to its anti-PD-1 candidate, tislelizumab. (See BioWorld, July 7, 2017.)

The Mirati deal shows that Beigene continues to work all the angles for tislelizumab in China, not content to wait and see what combos will turn up from Celgene's global pipeline for tislelizumab in solid tumors. "This collaboration complements our portfolio and will allow us to investigate sitravatinib in combination with tislelizumab, our investigational anti-PD-1 antibody, in China and the rest of the licensed territory," said John V. Oyler, founder, CEO and chairman of Beigene.

Playing the PD-1 versatility game

Beigene is aiming to position tislelizumab as the best-in-class PD-1, and barring that the best dance partner. The thinking is that it can set itself apart from the pack with an engineered Fc region that could minimize the negative interactions with other immune cells.

To date, tislelizumab has been dosed in more than 850 patients – in China and elsewhere – as either a monotherapy or part of a combination therapy

Early this month, a phase III combo trial kicked off – in collaboration with Celgene –for patients with previously untreated advanced hepatocellular cancer (HCC) to assess tislelizumab in a head-to-head comparison with Nexavar (sorafenib, Bayer AG), the current global standard of care for advanced liver cancer. The trial will enroll 640 patients at approximately 110 cancer centers in China, the U.S. and seven other countries. Patients will be randomized to receive either tislelizumab at 200 mg every three weeks or sorafenib at 400 mg twice daily.

The primary endpoint is overall survival, and secondary endpoints include overall response rate, progression-free survival, duration of response, time to progression, health-related quality of life, disease control rate, clinical benefit rate and safety profile.

"The expected median survival in patients with advanced liver cancer is typically less than one year, and patients can face difficulties tolerating sorafenib," said Qin Shukui, director of the Cancer Center at the People's Liberation Army 81 Hospital, Hospital deputy director and co-lead investigator of the trial. "I look forward to testing tislelizumab in the hopes that we can further advance treatment options for patients with advanced liver cancer."

HCC or liver cancer is tislelizumab's fourth indication. There are also two phase II China trials in relapsed/refractory classical Hodgkin lymphoma and urothelial cancer. Plus, a global phase III trial in patients with non-small-cell lung cancer (NSCLC).

Sitravatinib's potential in NSCLC

Sitravatinib (MGCD-0516) inhibits RTKs including RET, TAM family receptors (TYRO3, Axl, MER), and split family receptors (VEGFR2, KIT). It is being evaluated as a single agent in a phase 1b expansion trial enrolling patients that harbor RET, CHR4Q12 and CBL genetic alterations in NSCLC and other tumors.

In September, Mirati showed that sitravatinib and nivolumab in NSCLC patients with documented progression following checkpoint therapy demonstrated three confirmed partial responses in the first 11 evaluable patients. As a single agent, sitravatinib demonstrated in CBL patients a confirmed partial response with 77 percent tumor reduction, news that sent the firm's stock (NASDAQ:MRTX) jumping from $4.20 to $11.80. (See BioWorld, Sept. 18, 2017.)

The deal with Beigene saw Mirati's stock jump again from $19 on the day of the announcement to $27 at Thursday's close.

Mirati CEO and president, Charles M. Baum, said that Beigene's "ability to enroll patients quickly in a variety of indications will augment our development capabilities and expand the evaluation of sitravatinib to additional tumor types for patients who are checkpoint inhibitor-naïve or who have been previously treated with a checkpoint inhibitor."

Mirati plans to capitalize on the fact that China has long been a good place to find treatment-naïve patients.

Another Beigene strength that attracted Mirati's CEO to set up a China deal was Beigene's market preparedness.

"We are excited to begin a partnership with Beigene, which has built a world-class global development organization with a strong presence in Asia-Pacific, as well as an established commercial organization in China," said Baum.

An often overlooked aspect of the Beigene-Celgene deal is that the U.S.-based firm handed over its China commercial operation to Beigene, which is now selling Abraxane, (nab-paclitaxel), Revlimid (lenalidomide) and Vidaza (azacitidine) in China under a license from Celgene and has inherited the latter's sales force to boot.

In discussing the deal with BioWorld Asia, Oyler said at the time, "There are not many strong commercial organizations in China that are built and available. We expect to launch three of our own drugs in the next couple of years, by combining our pipeline with their [Celgene's] existing portfolio; we created an oncology sales organization with sufficient scale." Also in January, just after the sitravatinib deal, Beigene said it inked a deal for manufacturing tislelizumab in China in commercial quantities with Boehringer Ingelheim's Biopharmaceuticals (China) Ltd., a contract biologics manufacturer.

Beigene will work with BI under a market authorization holder (MAH) agreement, but the firm is also developing its own manufacturing capabilities in Guangzhou Development District, which will also be able to manufacture tislelizumab as well.

According to Jiali Lu, BI's China GM, that is the first MAH trial biopharmaceutical project for commercial supply in China.

With the recent regulatory reforms expected to open the floodgates of new drug approvals, there has been a rush to secure adequate biologics manufacturing. Beigene was one of the first to ink a deal with BI in China for smaller clinical trial quantities and has been focused on evolving itself into an integrated biopharma with an eye on to how to succeed in the market, not just the clinic.

"In the whole race to get a PD-1 approved, everyone talks about who will be first in China. But more need to consider who can actually manufacture it in a quality fashion," Oyler said.

Padding the coffers

On Jan. 17, Beigene announced plans for a follow-on share offering to the public of about 7.4 million American depositary shares (ADS) at a price to the public of $101 per ADS. The offering closed earlier this week, with the underwriters having the option to buy 495,050 additional shares at the public offering price for 30 days.

The offering raised about $800 million for Beigene to support working capital and research and development activities.

Goldman Sachs & Co. LLC, Morgan Stanley, Cowen and Leerink Partners acted as joint book-running managers, while William Blair & Co. LLC acted as the co-manager.

Beigene's stock (NASDAQ:BGNE) gained 15 percent since pricing the offering Jan. 17. Shares closed Monday at $118.26.

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